scholarly journals Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research

2021 ◽  
Vol 22 (2) ◽  
pp. 703
Author(s):  
Laura Baumgartner ◽  
Karin Wuertz-Kozak ◽  
Christine L. Le Maitre ◽  
Francis Wignall ◽  
Stephen M. Richardson ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
In Silico ◽  
Current Knowledge ◽  
Treatment Options ◽  
Cell Tissue ◽  
Advanced Therapies ◽  
Holistic Understanding ◽  
Health And Disease ◽  
In Silico Models ◽  
Ivd Degeneration

Intervertebral disc (IVD) degeneration is a major risk factor of low back pain. It is defined by a progressive loss of the IVD structure and functionality, leading to severe impairments with restricted treatment options due to the highly demanding mechanical exposure of the IVD. Degenerative changes in the IVD usually increase with age but at an accelerated rate in some individuals. To understand the initiation and progression of this disease, it is crucial to identify key top-down and bottom-up regulations’ processes, across the cell, tissue, and organ levels, in health and disease. Owing to unremitting investigation of experimental research, the comprehension of detailed cell signaling pathways and their effect on matrix turnover significantly rose. Likewise, in silico research substantially contributed to a holistic understanding of spatiotemporal effects and complex, multifactorial interactions within the IVD. Together with important achievements in the research of biomaterials, manifold promising approaches for regenerative treatment options were presented over the last years. This review provides an integrative analysis of the current knowledge about (1) the multiscale function and regulation of the IVD in health and disease, (2) the possible regenerative strategies, and (3) the in silico models that shall eventually support the development of advanced therapies.

F-actin cytoskeletal organization in intervertebral disc health and disease

2007 ◽  
Vol 35 (4) ◽  
pp. 683-685 ◽  
Author(s):  
S. Li ◽  
V.C. Duance ◽  
E.J. Blain
Keyword(s):  
Intervertebral Disc ◽  
Protein Trafficking ◽  
Current Knowledge ◽  
Cell Types ◽  
Filamentous Actin ◽  
Cellular Events ◽  
Disc Cells ◽  
Health And Disease ◽  
Cytoskeletal Networks ◽  
Review Current

The cytoskeleton, which in most cell types, including the intervertebral disc described here, comprises microfilaments, microtubules and intermediate filaments, plays important functions in many fundamental cellular events, including cell division, motility, protein trafficking and secretion. The cytoskeleton is also critical for communication; for example, alterations to the architecture of the F-actin (filamentous actin) cytoskeletal networks can affect communication between the cells and the extracellular matrix, potentially compromising tissue homoeostasis. Although there are limited studies to date, this paper aims to review current knowledge on F-actin cytoskeletal element organization in intervertebral disc cells, how F-actin differs with pathology and its implications for mechanotransduction.

scholarly journals Genetic Therapy for Intervertebral Disc Degeneration

2021 ◽  
Vol 22 (4) ◽  
pp. 1579 ◽  
Author(s):  
Eun Roh ◽  
Anjani Darai ◽  
Jae Kyung ◽  
Hyemin Choi ◽  
Su Kwon ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Animal Models ◽  
Intervertebral Disc ◽  
Treatment Options ◽  
Mammalian Target Of Rapamycin ◽  
Chronic Lower Back Pain ◽  
Technological Advances ◽  
Disc Cells ◽  
Ivd Degeneration

Intervertebral disc (IVD) degeneration can cause chronic lower back pain (LBP), leading to disability. Despite significant advances in the treatment of discogenic LBP, the limitations of current treatments have sparked interest in biological approaches, including growth factor and stem cell injection, as new treatment options for patients with chronic LBP due to IVD degeneration (IVDD). Gene therapy represents exciting new possibilities for IVDD treatment, but treatment is still in its infancy. Literature searches were conducted using PubMed and Google Scholar to provide an overview of the principles and current state of gene therapy for IVDD. Gene transfer to degenerated disc cells in vitro and in animal models is reviewed. In addition, this review describes the use of gene silencing by RNA interference (RNAi) and gene editing by the clustered regularly interspaced short palindromic repeats (CRISPR) system, as well as the mammalian target of rapamycin (mTOR) signaling in vitro and in animal models. Significant technological advances in recent years have opened the door to a new generation of intradiscal gene therapy for the treatment of chronic discogenic LBP.

scholarly journals Connecting Cancer Pathways to Tumor Engines: A Stratification Tool for Colorectal Cancer Combining Human In Vitro Tissue Models with Boolean In Silico Models

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 28 ◽  
Author(s):  
Florentin Baur ◽  
Sarah L. Nietzer ◽  
Meik Kunz ◽  
Fabian Saal ◽  
Julian Jeromin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
In Silico ◽  
Treatment Options ◽  
Braf Inhibitor ◽  
3D Models ◽  
Cancer Pathways ◽  
In Silico Models ◽  
Tissue Matrix ◽  
Tissue Models

To improve and focus preclinical testing, we combine tumor models based on a decellularized tissue matrix with bioinformatics to stratify tumors according to stage-specific mutations that are linked to central cancer pathways. We generated tissue models with BRAF-mutant colorectal cancer (CRC) cells (HROC24 and HROC87) and compared treatment responses to two-dimensional (2D) cultures and xenografts. As the BRAF inhibitor vemurafenib is—in contrast to melanoma—not effective in CRC, we combined it with the EGFR inhibitor gefitinib. In general, our 3D models showed higher chemoresistance and in contrast to 2D a more active HGFR after gefitinib and combination-therapy. In xenograft models murine HGF could not activate the human HGFR, stressing the importance of the human microenvironment. In order to stratify patient groups for targeted treatment options in CRC, an in silico topology with different stages including mutations and changes in common signaling pathways was developed. We applied the established topology for in silico simulations to predict new therapeutic options for BRAF-mutated CRC patients in advanced stages. Our in silico tool connects genome information with a deeper understanding of tumor engines in clinically relevant signaling networks which goes beyond the consideration of single drivers to improve CRC patient stratification.

scholarly journals Expression and activity of hyaluronidases HYAL-1, HYAL-2 and HYAL-3 in the human intervertebral disc

2019 ◽  
Vol 29 (3) ◽  
pp. 605-615 ◽  
Author(s):  
Olga Krupkova ◽  
Helen Greutert ◽  
Norbert Boos ◽  
Johannes Lemcke ◽  
Thomas Liebscher ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hyaluronic Acid ◽  
Intervertebral Disc ◽  
Protein Expression ◽  
Severe Group ◽  
Health And Disease ◽  
Catabolic Response ◽  
Donor Variation ◽  
Ivd Degeneration ◽  
Expression And Activity

Abstract Purpose Hyaluronic acid plays an essential role in water retention of the intervertebral disc (IVD) and thus provides flexibility and shock absorbance in the spine. Hyaluronic acid gets degraded by hyaluronidases (HYALs), and some of the resulting fragments were previously shown to induce an inflammatory and catabolic response in human IVD cells. However, no data currently exist on the expression and activity of HYALs in IVD health and disease. Methods Gene expression, protein expression and activity of HYALs were determined in human IVD biopsies with different degrees of degeneration (n = 50 total). Furthermore, freshly isolated human IVD cells (n = 23 total) were stimulated with IL-1β, TNF-α or H2O2, followed by analysis of HYAL-1, HYAL-2 and HYAL-3 gene expression. Results Gene expression of HYAL-1 and protein expression of HYAL-2 significantly increased in moderate/severe disc samples when compared to samples with no or low IVD degeneration. HYAL activity was not significantly increased due to high donor–donor variation, but seemed overall higher in the moderate/severe group. An inflammatory environment, as seen during IVD disease, did not affect HYAL-1, HYAL-2 or HYAL-3 expression, whereas exposure to oxidative stress (100 µM H2O2) upregulated HYAL-2 expression relative to untreated controls. Conclusion Although HYAL-1, HYAL-2 and HYAL-3 are all expressed in the IVD, HYAL-2 seems to have the highest pathophysiological relevance. Nonetheless, further studies will be needed to comprehensively elucidate its significance and to determine its potential as a therapeutic target. Graphic abstract These slides can be retrieved under Electronic Supplementary Material.

Pulmonary Manifestations in Rheumatoid Arthritis, Psoriatic Arthritis and Peripheral Spondyloarthritis Prevalence, Diagnostic Approach and Treatment Options

2020 ◽  
Vol 16 ◽  
Author(s):  
Daniel Dejcman ◽  
Valentin Sebastian Schäfer ◽  
Dirk Skowasch ◽  
Carmen Pizarro ◽  
Andreas Krause ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Psoriatic Arthritis ◽  
Lung Disease ◽  
Current Knowledge ◽  
Treatment Options ◽  
Pulmonary Diseases ◽  
Chronic Obstructive ◽  
Pulmonary Manifestations ◽  
Major Cluster ◽  
Peripheral Spondyloarthritis

: Interstitial lung disease (ILD) is the most common form of pulmonary impairment in patients with rheumatoid arthritis (RA). However, patients with RA or other arthritic diseases such as psoriatic arthritis (PsA) or peripheral spondyloarthritis (pSpA) may develop several other pulmonary diseases such as chronic obstructive lung disease (COPD) with a higher risk than patients without arthritis. The article at hand aims at summarizing the current knowledge on the prevalence of pulmonary diseases in the above-mentioned forms of arthritis, the challenges for prevalence studies and detecting pulmonary diseases in patients with arthritis as well as possible treatment options. Dyspnea, cough or other pulmonary symptoms or findings in arthritis patients should prompt gradual diagnostic procedures considering pulmonary manifestations as a major cluster of differential diagnosis. Considering its poor prognosis and morbidity burden, RA-ILD needs to be ruled out. Treatment of manifestations often lacks solid evidencebased guidelines and referrals to specialized centers are often necessary.

Immunotherapy and potential predictive biomarkers in the treatment of neuroendocrine neoplasia

2020 ◽  
Author(s):  
Guanghui Xu ◽  
Yuhao Wang ◽  
Hushan Zhang ◽  
Xueke She ◽  
Jianjun Yang
Keyword(s):  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
The Body ◽  
Low Grade ◽  
Ablative Therapies ◽  
Cancer Types ◽  
New Treatment ◽  
Well Differentiated

Neuroendocrine neoplasias (NENs) are a heterogeneous group of rare tumors scattered throughout the body. Surgery, locoregional or ablative therapies as well as maintenance treatments are applied in well-differentiated, low-grade NENs, whereas cytotoxic chemotherapy is usually applied in high-grade neuroendocrine carcinomas. However, treatment options for patients with advanced or metastatic NENs are limited. Immunotherapy has provided new treatment approaches for many cancer types, including neuroendocrine tumors, but predictive biomarkers of immune checkpoint inhibitors (ICIs) in the treatment of NENs have not been fully reported. By reviewing the literature and international congress abstracts, we summarize the current knowledge of ICIs, potential predicative biomarkers in the treatment of NENs, implications and efficacy of ICIs as well as biomarkers for NENs of gastroenteropancreatic system, lung NENs and Merkel cell carcinoma in clinical practice.

Neuroligin-2 as a central organizer of inhibitory synapses in health and disease

2020 ◽  
Vol 13 (663) ◽  
pp. eabd8379
Author(s):  
Heba Ali ◽  
Lena Marth ◽  
Dilja Krueger-Burg
Keyword(s):  
Synaptic Transmission ◽  
Synapse Formation ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Inhibitory Synapses ◽  
Molecular Architecture ◽  
Cellular Functions ◽  
Altered Expression ◽  
Health And Disease ◽  
Flow Of Information

Postsynaptic organizational protein complexes play central roles both in orchestrating synapse formation and in defining the functional properties of synaptic transmission that together shape the flow of information through neuronal networks. A key component of these organizational protein complexes is the family of synaptic adhesion proteins called neuroligins. Neuroligins form transsynaptic bridges with presynaptic neurexins to regulate various aspects of excitatory and inhibitory synaptic transmission. Neuroligin-2 (NLGN2) is the only member that acts exclusively at GABAergic inhibitory synapses. Altered expression and mutations in NLGN2 and several of its interacting partners are linked to cognitive and psychiatric disorders, including schizophrenia, autism, and anxiety. Research on NLGN2 has fundamentally shaped our understanding of the molecular architecture of inhibitory synapses. Here, we discuss the current knowledge on the molecular and cellular functions of mammalian NLGN2 and its role in the neuronal circuitry that regulates behavior in rodents and humans.

scholarly journals Targeting the Renin–Angiotensin–Aldosterone System to Prevent Hypertension and Kidney Disease of Developmental Origins

2021 ◽  
Vol 22 (5) ◽  
pp. 2298
Author(s):  
Chien-Ning Hsu ◽  
You-Lin Tain
Keyword(s):  
Kidney Disease ◽  
Current Knowledge ◽  
Current Evidence ◽  
Developmental Origins ◽  
Renin Angiotensin Aldosterone System ◽  
Renin Angiotensin ◽  
Health And Disease ◽  
Nitric Oxide Deficiency ◽  
Developing Kidney ◽  
Prevention Of Hypertension

The renin-angiotensin-aldosterone system (RAAS) is implicated in hypertension and kidney disease. The developing kidney can be programmed by various early-life insults by so-called renal programming, resulting in hypertension and kidney disease in adulthood. This theory is known as developmental origins of health and disease (DOHaD). Conversely, early RAAS-based interventions could reverse program processes to prevent a disease from occurring by so-called reprogramming. In the current review, we mainly summarize (1) the current knowledge on the RAAS implicated in renal programming; (2) current evidence supporting the connections between the aberrant RAAS and other mechanisms behind renal programming, such as oxidative stress, nitric oxide deficiency, epigenetic regulation, and gut microbiota dysbiosis; and (3) an overview of how RAAS-based reprogramming interventions may prevent hypertension and kidney disease of developmental origins. To accelerate the transition of RAAS-based interventions for prevention of hypertension and kidney disease, an extended comprehension of the RAAS implicated in renal programming is needed, as well as a greater focus on further clinical translation.

scholarly journals Stress-Related Dysfunction of Adult Hippocampal Neurogenesis—An Attempt for Understanding Resilience?

2021 ◽  
Vol 22 (14) ◽  
pp. 7339
Author(s):  
Julia Leschik ◽  
Beat Lutz ◽  
Antonietta Gentile
Keyword(s):  
Major Depression ◽  
Adult Neurogenesis ◽  
Current Knowledge ◽  
Functional Relation ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Special Focus ◽  
Extrinsic Cues ◽  
Health And Disease ◽  
Newborn Neurons

Newborn neurons in the adult hippocampus are regulated by many intrinsic and extrinsic cues. It is well accepted that elevated glucocorticoid levels lead to downregulation of adult neurogenesis, which this review discusses as one reason why psychiatric diseases, such as major depression, develop after long-term stress exposure. In reverse, adult neurogenesis has been suggested to protect against stress-induced major depression, and hence, could serve as a resilience mechanism. In this review, we will summarize current knowledge about the functional relation of adult neurogenesis and stress in health and disease. A special focus will lie on the mechanisms underlying the cascades of events from prolonged high glucocorticoid concentrations to reduced numbers of newborn neurons. In addition to neurotransmitter and neurotrophic factor dysregulation, these mechanisms include immunomodulatory pathways, as well as microbiota changes influencing the gut-brain axis. Finally, we discuss recent findings delineating the role of adult neurogenesis in stress resilience.

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